The overall objectives of this proposal are to design and test optimal strategies of cancer treatment in humans based on the concepts of the cell cycle and tumor cell population kinetics (Project A). Human tumors such as melanomas, carcinoma of the cervix, and epidermoid carcinoma of the head and neck are accessible for multiple biopsies and for growth kinetics studies such as cell cycle times and growth fractions. Our preliminary studies show that sequential and systematic kinetics analyses of biopsy specimens before, during, and after treatment with a single drug or radiation allow more accurate scheduling of subsequent agents and have led to improvements in response rates. Several intermediate research objectives will be concerned with the development of mathematical models and computational techniques to characterize human tumor growth and to predict and evaluate response to kinetics-based therapy (Project B). By using human tumor kinetics data obtained by FMF analysis in conjunction with appropriate mathematical models and computational techniques (which have been developed and described in Project B), one can readily determine the in vivo kinetics effects of drugs and radiation. Some treatment protocols developed from such modeling studies may depart radically from accepted standard treatment modalities and these will be tested in the 15091A anaplastic carcinoma model in A/J strain white mice (Project C). In addition, this animal model will be used to further characterize and explore the kinetics effects of drugs, radiation and hyperthermia combinations, and fractionations. Our overall goals, therefore, are to expand our kinetics studies in human tumors; to obtain more accurate data on recruitment and synchrony; and to develop kinetics-based mathematical models which will be used for the design of more effective treatment protocols.